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Topical treatment with inhibitors of the phosphatidylinositol 3'-kinase/Akt and Raf/mitogen-activated protein kinase kinase/extracellular signal-regulated kinase pathways inhibited the growth of TPras transgenic melanomas in severe combined immunodeficient mice, blocked invasive behavior, and reduced angiogenesis. The inhibitor Ly294002, which is specific for phosphatidylinositol 3'-kinase, effectively reduced melanoma cell growth both in vitro and in vivo. Both Ly294002 and U0126, a mitogen-activated protein kinase kinase 1/2 inhibitor, reduced invasion, which correlated with reduction of the metalloproteinase matrix metalloproteinase 2. Tumor angiogenesis was disrupted through inhibition of vascular endothelial growth factor production from the tumor cells and antiangiogenic effects on endothelial cells. Observations with TPras melanoma cells that express dominant negative Deltap85 or kinase-inactive Raf(301) supported the specificity of the phenomena observed with the chemical inhibitors. These studies demonstrate that topical treatment targeting Ras effectors is efficacious, without systemic toxicities, and may prove to be useful in treating and preventing the progression of cutaneous melanoma.

Type

Journal article

Journal

Cancer Res

Publication Date

01/04/2004

Volume

64

Pages

2552 - 2560

Keywords

Administration, Topical, Animals, Butadienes, Chromones, Down-Regulation, Endothelium, Vascular, Enzyme Inhibitors, MAP Kinase Kinase Kinases, MAP Kinase Signaling System, Male, Matrix Metalloproteinase 2, Melanoma, Experimental, Mice, Mice, SCID, Morpholines, Neovascularization, Pathologic, Nitriles, Phosphatidylinositol 3-Kinases, Protein-Serine-Threonine Kinases, Proto-Oncogene Proteins, Proto-Oncogene Proteins c-akt, Proto-Oncogene Proteins c-raf, Vascular Endothelial Growth Factor A